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I am learning about oxidative phosphorylation in cellular respiration now and do not understand the roles of complexes 2 and 3 in the process. Specifically, my textbook says that 2 and 3 pump H+ out into the inter-membrane space, just like complex 1 does.

Complex 1 pumps out the H+ from NADH, and I suppose that 2 would be needed to pump out the H+ from FADH2, but then why do we need complex 3? All the H+ has been pumped out already--there's none left!

Also, if this understanding were correct, there would be no purpose for the chain that started with NADH to go through complex 2 at all (because it already went through 1, as opposed to the chain starting with FADH2).

Thanks in advance for any clarification you can give.

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  • $\begingroup$ Complex II does not pump H+. What textbook are you using? $\endgroup$
    – Roland
    Nov 15 '15 at 9:39
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    $\begingroup$ "Chemistry: The Central Science, 13th edition". $\endgroup$
    – Jo.P
    Nov 15 '15 at 14:28
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The numbering of the complexes in the respiratory chain is confusing, as it creates the impression that the chain is structured like

Complex I $\rightarrow$ Complex II $\rightarrow$ Complex III $\rightarrow$ Complex IV

... but this is wrong. There are in fact several ways of feeding electrons into the respiratory chain. They all begin with one enzyme E that oxidizes an electron carrier in the mitochondrial matrix, such as NADH, FADH2, or ETF (electron transfer flavoprotein) and transfers electrons to coenzyme Q, which is then processed by Complex III, after which electrons are handed on to Complex IV. Both complex III and IV pump protons. But there are several options for the first enzyme E:

  • Complex I (NADH dehydrogenase). This handles all electrons from NADH (from many sources in oxidative metabolism) and is typically the major source of electrons in the chain. It is the only enzyme E that also pumps protons itself.
  • Complex II (succinate dehydrogenase) accepts electrons from succinate (a step in the TCA cycle).
  • ETF dehydrogenase accepts electrons from reduced ETF, notably from fatty acid oxidation.
  • Glycerol-3-phosphate dehydrogenase accepts electrons from cytosolic NADH (from glycolysis) via the glycorol-3-phosphate shuttle.

There are more alternatives, but I think these are the most important ones. So you are absolutely correct that when NADH is the substrate, Complex II is not involved. There is in fact not one respiratory chain, but several possible chains with different starting points E,

E $\rightarrow$ Complex III $\rightarrow$ Complex IV

You might think of this as a "fan in" structure where the various enzymes E all converge on Complex III. (I don't have the energy to draw this :)

As for the proton pumping at Complex III, it is not the case that the H$^+$ pumped are exactly those derived from NADH --- the system is more complicated than that. The respiratory chain(s) convert chemical energy from the redox reactions into potential energy (a proton gradient), but most of the H$^+$ pumped are obtained from the mitochondrial matrix. The exact number of protons varies depending on the substrate: for example, the 2 electrons donated by NADH at Complex I is sufficient to pump up to 10 protons. Actually, the stoichiometry is not fully understood, and there isn't really an exact integer number of H+ pumped, because this pumping is an imperfect physical process --- there is leakage, protins slipping back into the matrix etc.

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Complex 1 pumps protons, but Complex 2 does not. Both, however, take electrons from the electron carriers (NADH, and FADH2) and transport them inside the membrane to Complex 3. At Complex 3, the electrons are transferred via the Q-cycle to Cytochrome C which resides on the exterior of the membrane. In the process of transferring the electrons to Cytochrome C, Complex 3 also pumps protons. Cytochrome C moves from Complex 3 to Complex 4, where Oxygen functions as the final electron acceptor, while more protons are pumped.

Also a little clarification, Complex 1 and Complex 2 both donate the electrons to coenzyme Q 10/ubiquinone which is solubilized in the membrane. Complex 1 does not donate its electrons to Complex 2. Coenzyme Q/ubiquinone is what enters Complex 3.

Edit:

Complex 2 only accepts electrons from succinate oxidation to fumarate. ETF, and Glycerol-3-Phosphate dehydrogenase function much like Complex 2 in that they donate electrons to coenzyme Q without pumping protons. However, unlike Complex 2, these two enzymes are not trans-membrane proteins. ETF is associated on the matrix side of the inner mitochondrial membrane, and Glycerol-3-phosphate is associated cytosolic side of the inner mitochondrial membrane.

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  • $\begingroup$ I think this is inaccurate on Complex II, it is not a generic acceptor of reduced FAD. As I understand it, complex II contains a bound FAD cofactor, but this functions like prosthetic group and is exclusively devoted to oxidizing succinate; it cannot accept reduced FAD from other sources. FAD from fatty oxidation, for example, goes via ETF dehydrogenase. $\endgroup$
    – Roland
    Nov 15 '15 at 9:35

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